This randomized phase II trial studies how well carboplatin and combination chemotherapy with or without veliparib works in treating patients with stage IIB-IIIC breast cancer. Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin hydrochloride, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving carboplatin and combination chemotherapy are more effective with or without veliparib is more effective in treating breast cancer.

An Adaptive, Randomized Phase II Trial to Determine Pathologic Complete Response With the Addition of Carboplatin With and Without Veliparib to Standard Chemotherapy in the Neoadjuvant Treatment of Triple-Negative Breast Cancer

Pathologic complete response (PCR) [ Time Frame: At the time of surgery ] [ Designated as safety issue: No ]

PCR is defined as the absence of any residual invasive cancer on hematoxylin and eosin (H&E) evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes. The posterior distribution of the odds ratio will be used to assess whether carboplatin and/or carboplatin +veliparib in combination with paclitaxel has a higher PCR compared to each other and simulations will be used to compare to paclitaxel alone. A 95% credible region will be calculated for the odds ratio comparing the two combination treatments, the odds ratio comparing each treatment to paclitaxel alone, the PCR for each treatment regimen, for the difference in the PCR between each combination regimen, and the difference of each combination regimen to paclitaxel alone.

Secondary Outcome Measures:

Overall clinical response [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

The proportion of subjects with each category of overall clinical response will be summarized by presence of baseline measureable disease (i.e., complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD], unable to evaluate [UE], neurogenerative disease [ND]). Beta will be used as priors for combination regimens in calculating the posterior distribution of the PCR for each respective treatment group. Among subjects with measurable disease, a 95% credible region will be calculated for the odds ratio for each treatment combination relative to each other.

Relapse free survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

Analyzed using Kaplan-Meier methods, stratified by study group, and the log rank test will be completed.

Patients receive paclitaxel IV and carboplatin IV on day 1 (course 1 only) or day 2 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Drug: Paclitaxel

Given IV

Other Names:

Taxol

Abraxane

Drug: Carboplatin

Given IV

Other Names:

cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II)

Paraplatin

Paraplatin-AQ

Drug: Doxorubicin

Given IV

Other Names:

Adriamycin

hydroxydaunorubicin

Adriamycin PFS

Adriamycin RDF

Rubex

Doxil

Drug: Cyclophosphamide

Given IV

Other Names:

Endoxan

Cytoxan

Neosar

Procytox

Revimmune

cytophosphane

Lyophilizedcytoxan

Experimental: Arm 2 (veliparib, paclitaxel, carboplatin)

Patients receive veliparib PO BID on days 1-5. Patients also receive paclitaxel IV and carboplatin IV on day 3 (course 1 only) or day 4 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

1) To compare the pathologic complete response (path CR) in patients with stage IIB or stage III triple negative breast cancer treated with neoadjuvant paclitaxel and carboplatin to the path CR of patients treated with paclitaxel, carboplatin, and veliparib.

SECONDARY OBJECTIVES:

Relapse free survival (follow-up period of 36 months).

Overall clinical response to neoadjuvant therapy.

To determine whether expression of 5 biomarkers (cytokeratin [CK]5, endothelial growth factor receptor [EGFR], excision repair cross complementing 1 [ERCC1], Ki67, poly[adenosine diphosphate (ADP)-ribosyl]transferase [Parp1]) correlate with a higher pCR in response to a particular treatment combination. 4) To determine whether tumors with biomarker signatures that are most like breast cancer (BRCA)-mutated tumors (high expression of CK5 and high expression of EGFR), will correlate with a higher likelihood of pCR with treatment with a PARP inhibitor in combination with chemotherapy.

5) To determine whether tumors with high expression of the markers ERCC1, Ki67, and Parp1 will correlate with a higher rate of pCR with platinum agents in combination with paclitaxel or a PARP inhibitor.

To determine which arms are best tolerated by patients with co-morbid conditions, such as hypertension and diabetes.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel intravenously (IV) and carboplatin IV on day 1 (course 1 only) or day 2 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive veliparib orally (PO) twice daily (BID) on days 1-5. Patients also receive paclitaxel IV and carboplatin IV on day 3 (course 1 only) or day 4 (courses 2-12). Treatment repeats every 7 days for 12 courses in the absence of disease progression or unacceptable toxicity. Beginning 21 days after the last course, patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 36 months.

Eligibility

Ages Eligible for Study:

18 Years and older (Adult, Senior)

Genders Eligible for Study:

Female

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Written informed consent must be obtained prior to any study-related procedures.

Histologically confirmed adenocarcinoma of the breast with the following markers: Estrogen receptor negative (<1%), progesterone receptor negative (<1%), and Her-2/neu negative (Her-2/neu 0-1+ IHC or FISH ratio <1.8 or average HER2 gene copy number of <four signal/nucleus for test systems without internal control probe).

Not willing to use a highly effective method of birth control (i.e. those which result in low failure rates, less than 1% per year), defined as intrauterine devices, barrier methods (condoms, contraceptive sponges, diaphragms, vaginal rings used with spermicidal jellies or creams), oral contraceptive pills, or sexual abstinence. Contraception must be used during the study.

T0 tumors

Active dental infection

Contacts and Locations

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01818063